Central respiratory rhythmogenesis is abnormal in lbx1- deficient mice.
Lbx1 is a transcription factor that determines neuronal cell fate and identity in the developing medulla and spinal cord. Newborn Lbx1 mutant mice die of respiratory distress during the early postnatal period. Using in vitro brainstem-spinal cord preparations we tested the hypothesis that Lbx1 is necessary for the inception, development and modulation of central respiratory rhythmogenesis. The inception of respiratory rhythmogenesis at embryonic day 15 (E15) was not perturbed in Lbx1 mutant mice. However, the typical age-dependent increase in respiratory frequency observed in wild-type from E15 to P0 was not observed in Lbx1 mutant mice. The slow respiratory rhythms in E18.5 Lbx1 mutant preparations were increased to wild-type frequencies by application of substance P, thyrotropin releasing hormone, serotonin, noradrenaline, or the ampakine drug 1-(1,4-benzodioxan-6-yl-carbonyl) piperidine. Those data suggest that respiratory rhythm generation within the pre-Bötzinger complex (preBötC) is presumably functional in Lbx1 mutant mice with additional neurochemical drive. This was supported by anatomical data showing that the gross structure of the preBötC was normal, although there were major defects in neuronal populations that provide important modulatory drive to the preBötC including the retrotrapezoid nucleus, catecholaminergic brainstem nuclei, nucleus of the solitary tract, and populations of inhibitory neurons in the ventrolateral and dorsomedial medullary nuclei. Finally, we determined that those defects were caused by abnormalities of neuronal specification early in development or subsequent neuronal migration.
Pagliardini
Silvia
S
Department of Physiology, Centre for Neuroscience, University of Alberta, Edmonton, Alberta, Canada T6G2S2.
Ren
Jun
J
Gray
Paul A
PA
Vandunk
Cassandra
C
Gross
Michael
M
Goulding
Martyn
M
Greer
John J
JJ
D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D017763:Autonomic Denervation / Q000379:methods; D002395:Catecholamines / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003964:Diaphragm / Q000503:physiopathology; D004576:Electromyography; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D005998:Glycine / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D066298:In Vitro Techniques; D008526:Medulla Oblongata / Q000166:cytology / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000172:deficiency*; D009474:Neurons / Q000145:classification / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000494:pharmacology; D051762:PAX2 Transcription Factor / Q000378:metabolism; D010507:Periodicity; D010991:Plethysmography / Q000379:methods; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D012125:Respiratory Center / Q000002:abnormalities* / Q000187:drug effects / Q000378:metabolism; D015656:Respiratory Mechanics / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000196:embryology / Q000503:physiopathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D002395:Catecholamines; C491868:Lbx1h protein, mouse; D009124:Muscle Proteins; D018377:Neurotransmitter Agents; D051762:PAX2 Transcription Factor; C497319:Pax2 protein, mouse; D018040:Receptors, Neurokinin-1; D049452:Green Fluorescent Proteins; D014446:Tyrosine 3-Monooxygenase; D002795:Choline O-Acetyltransferase; D005998:Glycine